Poor Sleep Linked with Future Amyloid-β Build Up

by Abby Olena

There’s evidence in people and animals that short-term sleep deprivation can change the levels of amyloid-β, a peptide that can accumulate in the aging brain and cause Alzheimer’s disease. Scientists now show long-term consequences may also result from sustained poor sleep. In a study published September 3 in Current Biology, researchers found that healthy individuals with lower-quality sleep were more likely to have amyloid-β accumulation in the brain years later. The study could not say whether poor sleep caused amyloid-β accumulation or vice versa, but the authors say that sleep could be an indicator of present and future amyloid-β levels.

“Traditionally, sleep disruptions have been accepted as a symptom of Alzheimer’s disease,” says Ksenia Kastanenka, a neuroscientist at Massachusetts General Hospital who was not involved in the work. Her group showed in 2017 that improving sleep in a mouse model of Alzheimer’s disease, in which the animals’ slow wave sleep is disrupted as it usually is in people with the disease, halted disease progression.

Collectively, the results from these studies and others raise the possibility that “sleep rhythm disruptions are not an artifact of disease progression, but actually are active contributors, if not a cause,” she says, hinting at the prospect of using these sleep measures as a biomarker for Alzheimer’s disease.

As a graduate student at the University of California, Berkeley, Joseph Winer, who is now a postdoc at Stanford University, and his colleagues were interested in whether or not sleep could predict how the brain changes over time. They collaborated with the team behind the Berkeley Aging Cohort Study, which includes a group of 32 cognitively healthy adults averaging about 75 years of age. They participated in a sleep study, then had periodic cognitive assessments and between two and five positron emission tomography (PET) scans to check for the presence of amyloid-β in their brains for an average of about four years after the sleep study.

The researchers found at their baseline PET scan, which happened within six months of their sleep study, that 20 of the 32 participants already had some amyloid-β accumulation, which was not unexpected based on their average age. They also showed that both slow wave sleep, an indicator of depth of sleep, and sleep efficiency, the amount of time sleeping compared to time in bed, were both predictive of the rate of amyloid change several years later. In other words, people with lower levels of slow wave sleep and sleep efficiency were more likely to have faster amyloid build up.

The subjects all remained cognitively healthy over the duration of the study, says Winer. “We do expect that they’re at higher risk for developing Alzheimer’s in their lifetime because of the amyloid plaque.”

The strengths of the study include the well-characterized participants with detailed sleep assessments, as well as cognitive testing and longitudinal amyloid PET imaging, says Brendan Lucey, a sleep neurologist at Washington University in St. Louis who did not participate in the work.

There are still open questions about the link between sleep and amyloid deposition over time. “Amyloid accumulation on PET increases at different rates in amyloid-negative and amyloid-positive individuals, and even within amyloid-positive individuals,” Lucey explains. “Without adjusting for participants’ starting amyloid [levels], we don’t know if some participants would have been more likely to have increased amyloid compared to others, independent of sleep.”

“It is very hard to untangle this question of baselines,” acknowledges Winer. Because the sleep measures the team identified in the study are related to amyloid levels, to actually tease apart the effect of sleep quality on amyloid deposition and vice versa, it’d be necessary to study people starting as early as their fifties, when they’re much less likely to have amyloid accumulation, he says.

This study is “a great start,” David Holtzman, a neurologist and collaborator of Lucey at Washington University in St. Louis who did not participate in the work, tells The Scientist. In addition to controlling for the amount of amyloid deposition that is present in a subject’s brain at the beginning of the study, it would be important to see if the findings bear out in larger numbers of people and what role genetic factors play.

“The most important question down the road is to test the idea in some sort of a treatment paradigm,” Holtzman adds. “You can do something to improve the quality of sleep or increase slow wave sleep, and then determine if it actually slows down the onset of Alzheimer’s disease clinically.”

J.R. Winer et al., “Sleep disturbance forecasts β-amyloid accumulation across subsequent years,” Current Biology, doi:10.1016/j.cub.2020.08.017, 2020.

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Long-term usage of antidepressant medications may protect from dementia

Long-term treatment with certain antidepressants appeared associated with reduced dementia incidence, according to results of a case-control study published in Journal of Clinical Psychiatry.

“Depression could represent one of these potentially modifiable risk factors for all-cause dementia,” Claudia Bartels, PhD, of the department of psychiatry and psychotherapy at University Medical Center Goettingen in Germany, and colleagues wrote. “Numerous studies have concordantly demonstrated a strong association between depression and an increased risk [for] subsequent dementia. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depressive symptoms in [Alzheimer’s disease] dementia.

“Preclinical research in recent years has suggested that SSRIs reduce amyloid plaque burden in transgenic mouse models of [Alzheimer’s disease] and in cognitively healthy humans, attenuate amyloid-[beta]1-42–induced tau hyperphosphorylation in cell culture and improve cognition in mice.”

However, the effects of SSRIs on cognition in Alzheimer’s disease dementia were linked mostly to negative results in randomized clinical trials; research is sparse regarding which antidepressants may influence risk for developing dementia; and evidence is particularly rare for treatment duration effects on this risk. Thus, Bartels and colleagues sought to determine the effects of antidepressant drug classes and individual compounds with various treatment durations on the risk for developing dementia. The researchers analyzed data of 62,317 individuals with an incident dementia diagnosis who were included in the German Disease Analyzer database, and they compared outcomes to those of controls matched by age, sex and physician. They conducted logistic regression analyses, which were adjusted for health insurance status and comorbid diseases linked to dementia or antidepressant use, to evaluate the association between dementia incidence and treatment with four major classes of antidepressant drug, as well as 14 of the most commonly prescribed individual antidepressants.

Results showed an association between treatment for 2 years or longer with any antidepressant and a lower risk for dementia vs. short-term treatment among 17 of 18 comparison. Particularly for long-term treatment, herbal and tricyclic antidepressants were linked to a decrease in incidence of dementia. Long-term treatment with escitalopram (OR = 0.66; 95% CI, 0.5-0.89) and Hypericum perforatum (OR = 0.6; 95% CI, 0.51-0.7) were associated with the lowest risks for dementia on an individual antidepressant basis.

“Clinical trials — although well acknowledged as the gold standard procedure — have debunked numerous promising compounds and become increasingly challenging with longer treatment durations,” Bartels and colleagues wrote. “Thus, and in awareness of the controversy of this suggestion, analyzing data from registries in a naturalistic setting may be an attractive and feasible alternative. If individual datasets could be combined in a multinational effort, even more powerful analyses of merged big databases could be performed and an additive contribution with naturalistic data could be made.”

https://www.healio.com/news/psychiatry/20200828/longterm-treatment-with-certain-antidepressants-may-reduce-dementia-incidence

Alzheimer’s risk factors may be measurable in adolescents and young adults

Risk factors for Alzheimer’s dementia may be apparent as early as our teens and 20s, according to new research reported at the Alzheimer’s Association International Conference® (AAIC®) 2020.

These risk factors, many of which are disproportionately apparent in African Americans, include heart health factors — such as high blood pressure, high cholesterol and diabetes — and social factors like education quality. According to the Alzheimer’s Association Alzheimer’s Disease Facts and Figures report, older African Americans are about twice as likely to have Alzheimer’s or other dementias as older whites.

“By identifying, verifying, and acting to counter those Alzheimer’s risk factors that we can change, we may reduce new cases and eventually the total number of people with Alzheimer’s and other dementia,” said Maria C. Carrillo, Ph.D., Alzheimer’s Association chief science officer. “Research like this is important in addressing health inequities and providing resources that could make a positive impact on a person’s life.”

“These new reports from AAIC 2020 show that it’s never too early, or too late, to take action to protect your memory and thinking abilities,” Carrillo said.

The Alzheimer’s Association is leading the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), a two-year clinical trial to evaluate whether lifestyle interventions that simultaneously target many risk factors protect cognitive function in older adults who are at increased risk for cognitive decline. U.S. POINTER is the first such study to be conducted in a large, diverse group of Americans across the United States.

African American Youth At Higher Risk of Dementia

In a population of more than 714 African Americans in the Study of Healthy Aging in African Americans (STAR), Kristen George, Ph.D., MPH, of the University of California, Davis, and colleagues found that high blood pressure and diabetes, or a combination of multiple heart health-related factors, are common in adolescence and are associated with worse late-life cognition. Study participants were adolescents (n=165; ages 12-20), young adults (n=439; ages 21-34) and adults (n=110; ages 35-56). Mean age at cognitive assessment was 68.

Cognition was measured using in-person tests of memory and executive function. The researchers found that, in this study population, having diabetes, high blood pressure, or two or more heart health risk factors in adolescence, young adulthood, or mid-life was associated with statistically significantly worse late-life cognition. These differences persisted after accounting for age, gender, years since risk factors were measured, and education.

Before this report, little was known about whether cardiovascular disease (CVD) risk factors developed prior to mid-life were associated with late-life cognition. This is an important question because African Americans have a higher risk of CVD risk factors compared to other racial/ethnic groups from adolescence through adulthood.

According to the researchers, these findings suggest that CVD risk factors as early as adolescence influence late-life brain health in African Americans. Efforts to promote heart and brain healthy lifestyles must not only include middle-aged adults, but also younger adults and adolescents who may be especially susceptible to the negative impact of poor vascular health on the brain.

Early Adult BMI Associated With Late Life Dementia Risk

In what the authors say is the first study to report on the issue, higher early adulthood (age 20-49) body mass index (BMI) was associated with higher late-life dementia risk.

Relatively little is known about the role of early life BMI on the risk of Alzheimer and other dementias. The scientists studied a total of 5,104 older adults from two studies, including 2,909 from the Cardiovascular Health Study (CHS) and 2,195 from the Health, Aging and Body Composition study (Health ABC). Of the total sample, 18% were Black and 56% were women. Using pooled data from four established cohorts spanning the adult life course, including the two cohorts under the study, the scientists estimated BMI beginning at age 20 for all older adults of CHS and Health ABC.

For women, dementia risk increased with higher early adulthood BMI. Compared to women with normal BMI in early adulthood, dementia risk was 1.8 times higher among those who were overweight, and 2.5 times higher among those who were obese. Analyses were adjusted for midlife and late life BMI.

They found no association between midlife BMI and dementia risk among women.

For men, dementia risk was 2.5 times higher among those who were obese in early adulthood, 1.5 times higher among those who were overweight in mid-life and 2.0 times higher among those who were obese in mid-life, in models also adjusted for late life BMI.

For both women and men, dementia risk decreased with higher late life BMI.

Adina Zeki Al Hazzouri, Ph.D. of Columbia University and colleagues found that high BMI in adulthood is a risk factor for dementia in late life. The researchers suggest that efforts aimed at reducing dementia risk may need to begin earlier in life with a focus on obesity prevention and treatment.

Quality of Early-Life Education Influences Dementia Risk

In a diverse group of more than 2,400 people followed up to 21 years, higher quality early-life education was associated with better language and memory performance, and lower risk of late-life dementia. Results were somewhat different between men and women, and between Blacks and Whites in the study.

The study included 2,446 Black and White men and women, age 65 and older, enrolled in the Washington Heights/Inwood Columbia Aging Project who attended elementary school in the United States. A school quality variable based on historical measures included: mandatory school enrollment age, minimum dropout age, school term length, student-teacher ratio, and student attendance.

People who attended school in states with lower quality education had more rapid decline in memory and language as an older adult. Black women and men and White women who attended schools in states with higher quality education were less likely to develop dementia. According to the scientists, the results were explained, in part, because people who attend higher quality schools end up getting more years of school.

Justina Avila-Rieger, PhD, a postdoctoral research scientist at Columbia University Irving Medical Center and colleagues say the findings provide evidence that later life dementia risk and cognitive function is influenced by early-life state educational policies.

https://www.sciencedaily.com/releases/2020/07/200730092616.htm

Experimental Blood Test Could Flag Alzheimer’s


New studies show that elevated levels of a form of tau called p-tau217 can accurately distinguish Alzheimer’s disease from other forms of dementia, and perhaps even predict it.

by Kerry Grens

Three studies presented at the Alzheimer’s Association International Conference this week describe the performance of blood tests used to diagnose, and even predict, Alzheimer’s disease using circulating levels of a form of tau protein called p-tau217. The largest assessment of this approach, which included 1,402 participants, showed that circulating p-tau217 levels worked just as well at detecting Alzheimer’s as standard PET scans and tests of cerebrospinal fluid.

“This blood test very, very accurately predicts who’s got Alzheimer’s disease in their brain, including people who seem to be normal,” Michael Weiner, an Alzheimer’s disease researcher at the University of California, San Francisco, who was not involved in the study, tells The New York Times. “It’s not a cure, it’s not a treatment, but you can’t treat the disease without being able to diagnose it. And accurate, low-cost diagnosis is really exciting, so it’s a breakthrough.”

A blood test could help identify people on track to develop Alzheimer’s early on—and perhaps get them enrolled in drug trials aimed at finding an effective treatment for the disease. Scientists have pursued a number of potential circulating biomarkers, such as amyloid-β, to find those that can reliably diagnose Alzheimer’s disease or predict its development, but to date none have come to market.

High levels of tau or its phosphorylated form, p-tau, have emerged as promising biomarker candidates because they may indicate the presence of damaging structures known as neurofibrillary tangles in the brain.

The large study on one type of p-tau, p-tau217, published in JAMA July 28 to coincide with the presentation at the meeting, was a collection of three experiments using a blood test developed by Eli Lilly (some of the coauthors work for the company). In one assessment of several hundred Swedes, the test accurately distinguished patients who had Alzheimer’s from those with other forms of dementia with 89–98 percent accuracy. “That’s pretty good. We’ve never seen that” precision before, Maria Carrillo, the Alzheimer’s Association’s chief science officer, tells the Associated Press.

In another assessment of the Eli Lilly test, which included hundreds of related individuals, some of whom have a gene that causes Alzheimer’s, p-tau217 levels in the blood aligned with the genetics, even decades before cognitive impairment is likely to begin.

Another study presented at the conference found a p-tau217 blood test could accurately distinguish Alzheimer’s patients from those with frontotemporal lobar degeneration, according to a conference press release. And a third presentation of a study by Suzanne Schindler of Washington University in St. Louis and her colleagues reported that circulating p-tau217 was superior to another form that’s been studied as a potential biomarker, p-tau181, as a proxy for amyloid accumulation in the brain.

“I personally find it very reassuring that these different groups are using different types of assays and getting the same result,” Schindler tells the Times. “It looks real. It looks like 217 has tremendous promise as a blood test for Alzheimer’s disease, and it is likely to correspond with the symptoms.”

Speaking to The Guardian, Clive Ballard, who studies age-related disease at the University of Exeter Medical School and who was not involved in these projects, says, “further validation in people from more routine clinical settings are still needed, and a lot of work will be needed to achieve standardisation of the test across laboratories—so it could still be at least five years before we see an accurate blood biomarker test for dementia in the clinic.”

https://www.the-scientist.com/news-opinion/experimental-blood-test-could-flag-alzheimers-67779?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_medium=email&_hsmi=92321648&_hsenc=p2ANqtz-8ayk91AfO8kNKldfK3kfssyQf2GRuKPsOimQKjhl3hz5Ap-KFfFI0molaN5LwimzBJw9JHyX8TCowcon5V50G5hr5ErA&utm_content=92321648&utm_source=hs_email

Neupro may reduce cognitive dysfunction among patients with Alzheimer’s disease

The dopaminergic agonist Neupro appeared to improve frontal cognitive functions and activities of daily living among patients with mild to moderate Alzheimer’s disease, according to study results published in JAMA Network Open.

“Some early attempts have been carried out using dopaminergic drugs, such as L-dopa or selegiline, in samples of patients with Alzheimer’s disease at different stages of the disease, with some controversial results,” Giacomo Koch, MD, PhD, of the department of behavioral and clinical neurology at Santa Lucia Foundation Scientific Institute for Research, Hospitalization and Healthcare in Rome, and colleagues wrote. “More recently, experimental studies in animal models of Alzheimer’s disease showed that dopaminergic agonists may reduce amyloid deposition and improve memory and that the degeneration of dopaminergic neurons in the ventral tegmental area contributes to memory deficits. It has also been shown that in the early stages of Alzheimer’s disease, dopaminergic agonists improve cholinergic transmission and cortical plasticity likely by acting on the dopaminergic projections over the frontal cortex.”

This prior evidence suggested novel implications for therapies based on dopaminergic stimulation among patients with mild to moderate Alzheimer’s disease, according to the investigators. Thus, they sought to determine whether dopaminergic agonist therapy would affect cognitive functions among this patient population.

In the current phase 2, monocentric, randomized, double-blind, placebo-controlled trial conducted in Italy and funded by the Alzheimer’s Drug Discovery Foundation, Koch and colleagues enrolled 94 patients (mean age, 73.9 years) with mild to moderate Alzheimer’s disease between September 2017 and December 2018. The intervention comprised use of a Neupro (rotigotine, UCB) 2 mg transdermal patch for 1 week, followed by a 4 mg patch for 23 weeks among 47 patients or a placebo transdermal patch for 24 weeks among 47 patients. Change from baseline on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale served as the primary end point. Secondary end points included changes in Frontal Assessment Battery, Alzheimer’s Disease Cooperative Study-Activities of Daily Living and Neuropsychiatric Inventory scores. The researchers used transcranial magnetic stimulation combined with electroencephalography to evaluate prefrontal cortex activity.

A total of 78 patients completed the study. Results showed rotigotine compared with placebo had no significant effect on the primary end point, with an estimated mean change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale score of 2.92 (95% CI, 2.51-3.33) among the rotigotine group and 2.66 (95% CI, 2.31-3.01) among the placebo group. The researchers reported significant estimated mean changes for the secondary outcomes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score, which was 3.32 (95% CI, 4.02 to 2.62) among the rotigotine group and 7.24 (95% CI, 7.84 to 6.64) among the placebo group. Frontal Assessment Battery score was 0.48 (95% CI, 0.31-0.65) among the rotigotine group and 0.66 (95% CI, 0.80 to 0.52) among the placebo group. Koch and colleagues observed no longitudinal change in Neuropsychiatric Inventory scores for either group. Neurophysiological analysis of electroencephalography results revealed increased prefrontal cortical activity among the rotigotine group but not the placebo group. Patients in the rotigotine group were more likely to experience adverse events than the placebo group, and 11 patients dropped out compared with five, respectively.

“This study provides novel evidence that drugs acting on the dopaminergic system may be helpful to improve cognitive functions related to the frontal lobe activity,” Koch told Healio Psychiatry. “We hope that this research will expand Alzheimer’s disease therapy to drugs acting on different neurotransmission systems, such as the dopaminergic one, in addition to the cholinergic drugs.”

https://www.healio.com/news/psychiatry/20200715/neupro-may-reduce-cognitive-dysfunction-among-patients-with-alzheimers-disease?utm_source=ADDF&utm_campaign=e9d85ea654-EMAIL_CAMPAIGN_2019_11_18_10_21_COPY_01&utm_medium=email&utm_term=0_cc5f9da121-e9d85ea654-97060793

Higher BMI in early adulthood linked to increased dementia risk, new study suggests


Risk is 1.8 times higher for overweight women and 2.5 times higher for men

by Ella Pickover

People who are overweight in early adult life may be more prone to dementia in later life, a study suggests.

Those aged 20 to 49 who have a high body mass index have a higher risk of dementia later on, the authors said.

Researchers from Columbia University in the US studied data on more than 5,000 adults.

Compared with women who had a normal BMI, those who were overweight had a 1.8 times higher risk of dementia later on in life.

Obese women had a 2.5 times higher risk.

For men, dementia risk was 2.5 times higher among those who were obese in early adulthood, according to the findings presented to the Alzheimer’s Association International Conference.

An association was found between being overweight or obese in mid-life – classed in the study as people aged 50 to 69 – among men but not women.

Both men and women have a higher chance of dementia if they are obese in later life, the researchers found.

Commenting on the study, Dr Rosa Sancho, head of research at Alzheimer’s Research UK, said: “This study links a higher BMI in early adulthood with an increased risk of dementia later in life and underlines the importance of maintaining a healthy weight to help support a healthy brain.”

But more studies are needed to examine the link in more detail, she said, adding: “We know that diseases that cause dementia get under way in the brain many years before symptoms start to show. Studies looking at our lifestyle in early adulthood are important to help us build a picture of the factors that could impact our brain health as we age.”

Fiona Carragher, director of research and influencing at Alzheimer’s Society, added: “A healthy and balanced lifestyle is an important step towards reducing the risk of dementia later in life.

“Previous research we’ve supported, such as the 2017 Lancet commission, has shown that obesity in mid-life may increase dementia risk, so it’s interesting to see a study that shows this may also be the case in younger people too. But this can’t tell us if high BMI is a direct cause of dementia, there could be other factors at play.

“The number of people living with dementia is set to rise to one million by 2025 so it’s becoming increasingly urgent that we find ways to prevent people developing the condition in the first place.

“We can all take steps towards a healthy lifestyle, whether it’s by watching our diets or making the most of the sunny days and getting outside for a walk – it’s never too late, or early, to make a change.

“Research funding also plays a vital role here, hit badly by the current pandemic – so it’s critical that the government commits to their pledge to double life-saving research funding for the chronically under-funded field of dementia.”

https://www.independent.co.uk/news/uk/home-news/bmi-early-adulthood-increased-dementia-risk-us-a9645101.html

Alzheimer’s Drug Discovery Foundation (ADDF) and Harrington Discovery Institute Partnership Helps Move Promising Alzheimer’s Research from Bench toward Bedside


Research by 2015 ADDF-Harrington Scholar Jerri Rook, Ph.D. of Vanderbilt University leads to licensing agreement to develop drugs that improve memory.

A recently announced licensing agreement between drug maker Acadia Pharmaceuticals and Vanderbilt University represents a major milestone for the ADDF-Harrington Scholar Award Program, which provided funding and pharmaceutical expertise to support the research in the early phases. Acadia and Vanderbilt will collaborate to develop and commercialize novel drug candidates targeting synaptic receptors in the brain, long thought to play a key role in Alzheimer’s disease.

“This type of licensing agreement is precisely the goal of the ADDF-Harrington partnership,” said Dr. Andrew A. Pieper, Harrington Discovery Institute Director of Neurotherapeutic Discovery. “We bridge the gap between academia, where many great medical ideas are born, and industry, where these ideas can be guided through the costly and complex process of transforming them into new medicines for patients.”

Vanderbilt University principal investigator Jerri Rook, Ph.D. and her Vanderbilt University Medical Center physician collaborator Dr. Paul Newhouse received the 2015 ADDF-Harrington Scholar Award. The award provided funding and expertise in formulation and interpretation of safety pharmacology and toxicology data from experienced drug development professionals.

The compounds covered by the agreement work by activating muscarinic M1 receptors in the brain in a unique way that increases their responsiveness to a neurotransmitter called acetylcholine, which plays a critical role in regulating memory and cognition.

“We are excited about the commercial support for the important work of Dr. Rook and her colleagues that we hope will lead to an effective and safe treatment for people with Alzheimer’s disease,” said Dr. Howard Fillit, ADDF Founding Executive Director and Chief Science Officer.

As explained by Dr. Rook, researchers have long theorized that this mechanism could effectively treat memory loss in Alzheimer’s disease and other brain disorders, but intolerable side effects have barred their use—at least so far. “Our focus has been on discovering and developing compounds that have the desired treatment benefits without the unwanted side effects. We have now optimized this in a mouse model of Alzheimer’s disease and are very much looking forward to seeing how they perform in human studies,” said Dr. Rook. The lead compound has entered Phase I clinical trials with support from the ADDF.

About the Alzheimer’s Drug Discovery Foundation (ADDF)

The Alzheimer’s Drug Discovery Foundation is the only public charity solely focused on funding the development of drugs for Alzheimer’s disease, employing a venture philanthropy model to support research in academia and the biotech industry. Through the generosity of its donors, the ADDF has awarded more than $150 million to fund over 626 Alzheimer’s drug discovery programs and clinical trials in 19 countries. To learn more, please visit: https://www.alzdiscovery.org/.

About the Harrington Discovery Institute

The Harrington Discovery Institute at University Hospitals in Cleveland, Ohio—part of The Harrington Project for Discovery & Development—aims to advance medicine and society by enabling the most inventive scientists to turn their discoveries into medicines that improve human health. The Institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a “Better World.”

SOURCE Alzheimer’s Drug Discovery Foundation

https://www.prnewswire.com/news-releases/alzheimers-drug-discovery-foundation-addf-and-harrington-discovery-institute-partnership-helps-move-promising-alzheimers-research-from-bench-toward-bedside-301096316.html?tc=eml_cleartime

ADDF and Harrington Discovery Institute support novel research from Dr. Eugenia Trushina of Mayo Clinic Rochester to preserve aging neurons


Eugenia Trushina, PhD: Mitochondria as a Therapeutic Target for Alzheimer

The Alzheimer’s Drug Discovery Foundation (ADDF) and Harrington Discovery Institute at University Hospitals have granted Eugenia Trushina, Ph.D., of Mayo Clinic Rochester, the ADDF-Harrington Scholar Award.

Dr. Trushina has been awarded $600,000 for her late stage preclinical research on new drug candidates that show promise in restoring mitochondrial function. In addition to funding, she will receive in-depth drug development support to help maximize her project’s potential for clinical success.

“The ADDF-Harrington partnership helps scientists move academic discoveries from their labs toward clinical studies, and eventually into the clinic to improve the lives of people living with and at risk of Alzheimer’s,” said Dr. Howard Fillit, the ADDF’s Founding Executive Director and Chief Science Officer. “The mitochondria, which are the powerhouses of the cell, are a promising new target in the fight to combat this devastating disease.”

Dr. Trushina has shown that restoring function in mitochondria may delay the onset or slow the progression of Alzheimer’s disease. The compounds she and her team have developed have shown a positive effect in both symptomatic and pre-symptomatic models of Alzheimer’s.

“Supporting this innovative therapeutic approach for patients with Alzheimer’s disease represents our dedication to developing new classes of medicines that are not otherwise traditionally pursued in the field,” said Dr. Andrew Pieper, Director of the Neurotherapeutics Center of the Harrington Discovery Institute and University Hospitals Morley-Mather Chair in Neuropsychiatry.

Dr. Trushina’s research was selected through a competitive process, based on its potential to advance towards the clinic as a novel approach to treat, prevent, or cure Alzheimer’s disease and related dementias. Collaboration between the ADDF and Harrington Discovery Institute for this award provides recipients with both research funding and expert guidance in order to efficiently bridge the gap between academia and pharma.

“We are in our seventh year of collaborating with the ADDF to address this major unmet medical need,” said Jonathan Stamler, MD, President, Harrington Discovery Institute and Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair of Cardiovascular Innovation and Professor of Medicine at University Hospitals and Case Western Reserve University. “This partnership leverages our combined expertise and resources to give the science the best chance of advancing towards a cure for Alzheimer’s disease.”

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About the Alzheimer’s Drug Discovery Foundation (ADDF)

The Alzheimer’s Drug Discovery Foundation is dedicated to rapidly accelerating the discovery of drugs to prevent, treat and cure Alzheimer’s disease. The ADDF is the only public charity solely focused on funding the development of drugs for Alzheimer’s, employing a venture philanthropy model to support research in academia and the biotech industry. Through the generosity of its donors, the ADDF has awarded more than $150 million to fund over 626 Alzheimer’s drug discovery programs and clinical trials in 19 countries. To learn more, please visit: https://www.alzdiscovery.org/

About the Harrington Discovery Institute

The Harrington Discovery Institute at University Hospitals in Cleveland, Ohio–part of The Harrington Project for Discovery & Development–aims to advance medicine and society by enabling our nation’s most inventive scientists to turn their discoveries into medicines that improve human health. The institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a “Better World.”

About the Harrington Project for Discovery & Development

The Harrington Project for Discovery & Development (The Harrington Project), founded in late February 2012 by the Harrington Family and University Hospitals of Cleveland, is a $300 million national initiative built to bridge the translational valley of death. It includes the Harrington Discovery Institute and BioMotiv, a for-profit, mission-aligned drug development company that accelerates early discovery into pharma pipelines.

https://www.eurekalert.org/pub_releases/2020-07/addf-aah070720.php

Aerobic exercise limits risk of Alzheimer’s in vulnerable adults


A new study has found a new link between regular aerobic exercise and improved cognitive function in brain regions associated with Alzheimer’s disease.

By Nick Lavars

Previous research has shown us how regular exercise can be beneficial for cognitive function and help stave off the brain degeneration associated with dementia and Alzheimer’s, but scientists continue to learn more about the mechanisms at play. The latest discovery in this area comes courtesy of researchers from the University of Wisconsin (UW), who have published a new study describing a relationship between regular aerobic exercise and a reduced vulnerability to Alzheimer’s among high-risk adults.

More and more research is establishing stronger and stronger links between exercise and the prevention or slowing of Alzheimer’s and dementia. Last September, one study found that a regime of regular aerobic exercise could slow the degeneration of the hippocampus, while another from early in 2019 found that a hormone released during exercise can improve brain plasticity and memory.

For the new study, the UW researchers enlisted 23 subjects, with the participants all cognitively healthy young adults but with a heightened risk of Alzheimer’s due to family history and genetics. All lived what the researchers describe as a sedentary lifestyle and were first put through examinations to assess their cardiorespiratory fitness, cognitive function, typical daily physical activity, and brain glucose metabolism, which is considered a measure of neuronal health.

From there, half of the subjects were given information about how to lead a more active lifestyle, but were then left to their own devices. The other half of the group was given a personal trainer and put through a treadmill training program described as “moderate intensity,” involving three sessions a week across 26 weeks.

Unsurprisingly, the active group demonstrated improved cardio fitness and took on less sedentary lifestyles once the training program had finished. But in addition, they scored higher on cognitive tests of executive functioning, which is the capacity of the brain to plan, pay attention, remember instructions and multitask. Executive function is known to deteriorate during the onset of Alzheimer’s.

“This study is a significant step toward developing an exercise prescription that protects the brain against AD, even among people who were previously sedentary,” explains lead investigator Ozioma C. Okonkwo.

In addition to this improved executive function, brain scans also revealed some marked differences in brain glucose metabolism in the posterior cingulate cortex, a region again linked with Alzheimer’s.

“This research shows that a lifestyle behavior – regular aerobic exercise – can potentially enhance brain and cognitive functions that are particularly sensitive to the disease,” says Okonkwo. “The findings are especially relevant to individuals who are at a higher risk due to family history or genetic predisposition.”

With the sample size on the small side, the researchers are now working towards larger studies with more subjects to see if their findings can be replicated.

The research was published in the journal Brain Plasticity.

https://newatlas.com/medical/aerobic-exercise-risk-alzheimers-vulnerable-adults/

Visualization of rotein tangles in Alzheimer’s patients could help predict brain shrinkage


Pet scans comparing brains with Alzheimer’s with healthy brains. The researchers used PET scans to study the brains of 32 people with early Alzheimer’s. Photograph: Jonathan Selig/Getty Images
Research suggests tangles of tau could be used to predict how much shrinkage will occur and where

Tangles of a protein found inside the brain cells of people with Alzheimer’s disease can be used to predict future brain shrinkage, research suggests.

In healthy people, a protein called tau is important in supporting the internal structure of brain cells. However, in those with Alzheimer’s, chemical changes take place that cause the protein to form tangles that disrupt the cells. Such tangles have previously been linked to a loss of brain cells.

Now scientists have used imaging techniques to track the extent of tau tangles in the brains of those with early signs of Alzheimer’s, revealing that levels of the protein predict not only how much brain shrinkage will subsequently occur, but where.

“Our study supports the notion that tau pathology accumulates upstream of brain tissue loss and clinical symptoms,” said Prof Gil Rabinovici, a co-author of the research from the University of California, San Francisco.

A number of drugs targeting tau tangles are currently in clinical trials, including some that aim to interfere with the production of tau in the brain or its spread between cells.

Dr Renaud La Joie, another author of the research, said the findings suggested the imaging technique could prove valuable both in choosing which patients to enrol to test such drugs and in monitoring whether the drugs work.

Dr Laura Phipps, of Alzheimer’s Research UK, said: “The ability to track tau in the brain will be critical for testing treatments designed to prevent the protein causing damage, and the scans used in this study could be an important tool for future clinical trials.”

Writing in the journal Science Translational Medicine, La Joie and colleagues report how they used an imaging technique called positron emission tomography (Pet) to study the brains of 32 people aged between 49 and 83 who were in the early stages of showing Alzheimer’s symptoms.

Pet imaging involves injecting patients with a substance that contains a radioactive atom. The area in which the substance clusters shows up in subsequent scans.

The scientists used one substance that attaches to plaques of a protein in the brain known as beta amyloid, a hallmark of Alzheimer’s disease, and another recently developed substance that attaches to tau tangles.

They took a Pet scan at the start of the study, as well as an MRI, which reveals the structure of the brain. A second MRI was taken 15 months later to track brain atrophy.

The results reveal the level and location of tau tangles shown by the Pet scan at the outset were closely linked to shrinkage of grey matter in the brain, both in terms of the degree of shrinkage and its location. Such patterns explained about 40% of the variation in shrinkage. By contrast, there was little sign of a link between brain shrinkage and the extent of beta amyloid shown by Pet scan.

The findings held even when the thickness of the brain’s grey matter at the start of the study was taken into account, and when the age of participants was considered.

Although previous research has suggested brain atrophy shows a stronger link to tau tangles than beta amyloid, the team say the findings were still a surprise. “We were amazed by how well tau predicted not only the degree of atrophy overall, but the precise location of atrophy in individual patients,” said La Joie.

But, he added, the lack of a link to signs of beta amyloid does not mean those plaques are not harmful. “It is extremely rare to see significant amounts of tau tangles across the brain in patients with no amyloid: for some reason, amyloid seems almost necessary for tau to build up in the cortex,” said La Joie.

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The study has limitations, including that the Pet scan gives only an indirect measure of levels of tau and beta amyloid, and the tracking substances might not bind only to those proteins.

“This relatively small study adds to evidence that tau may drive the death of brain cells, and could explain why symptoms get worse as tau spreads through the brain,” said Phipps. “While the majority of volunteers in the study were under the age of 65, making it harder to generalise the findings to everyone with the disease, the study highlights the importance of focusing future research efforts on the tau protein.”

https://www.theguardian.com/science/2020/jan/01/protein-tangles-in-alzheimers-patients-could-help-predict-brain-shrinkage